title: The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis.
abstract: A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: Christopher
authors.initials: C
authors.lastname: Browning
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Buckley
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Clark
authors.forename: Lise
authors.initials: L
authors.lastname: Fechner
authors.forename: Paul M
authors.initials: PM
authors.lastname: Gore
authors.forename: Ashley P
authors.initials: AP
authors.lastname: Hancock
authors.forename: Simon T
authors.initials: ST
authors.lastname: Hodgson
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.forename: Michael
authors.initials: M
authors.lastname: Kranz
authors.forename: Brian E
authors.initials: BE
authors.lastname: Looker
authors.forename: Karen M L
authors.initials: KM
authors.lastname: Morriss
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Parton
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Russell
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Slack
authors.forename: Steven L
authors.initials: SL
authors.lastname: Sollis
authors.forename: Sadie
authors.initials: S
authors.lastname: Vile
authors.forename: Clarissa J
authors.initials: CJ
authors.lastname: Watts
mesh_terms: D000281:Administration, Intranasal; D000284:Administration, Oral; D055808:Drug Discovery / Q000379:methods*; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008958:Models, Molecular; D010793:Phthalazines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D011969:Receptors, Histamine H1 / Q000737:chemistry / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012220:Rhinitis / Q000188:drug therapy*
chemical_list: D006634:Histamine H1 Antagonists; D054828:Histamine H3 Antagonists; D010793:Phthalazines; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; C043388:phthalazine